A 2025 study found that PCX, a surface molecule on endometrial cells, may lead to a shorter implantation window in women with endometriosis and might explain the stickiness of lesions outside the uterus.
One of the big questions in fertility research is whether endometriosis affects the ability of the uterus to accept an embryo. Some studies suggest it does, while others say it doesn’t make much difference.
One possible reason for this confusion is that we don’t have great tools to measure how “ready” the uterus is to support implantation.
A new study by Samarajeewa et al. (2025) looked at a molecule called podocalyxin (PCX), which could serve as a useful marker to track when the uterus becomes receptive and when that window closes.
🔗 Original studies are referenced in this post or within the linked Remembryo posts.
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PCX is a protein that sits on the surface of cells and acts like a slippery coating. In the uterus, it helps prevent things from sticking to the surface, like an embryo trying to implant. It’s normally high at the start of the menstrual cycle and then goes down at the right time to allow the embryo to attach for implantation.
However, the timing is important! PCX needs to vanish at just the right time, and if the timing is off, the embryo might not stick or might implant at the wrong time.
The researchers wanted to see whether this carefully timed regulation of PCX was altered in women with endometriosis. To do this, they analyzed endometrial tissue from 41 women with endometriosis and 55 women without the condition, collecting samples across different phases of the menstrual cycle. This includes the proliferative, early secretory, mid-secretory, and late secretory phases. They used histological dating (from endometrial biopsies) to characterize these phases. They treated the mid-secretory phase as the receptive window for implantation, which typically corresponds to days 19–23 of a 28-day cycle.
The researchers focused on PCX levels in two types of endometrial cells:
- Surface epithelium: These cells line the surface of the endometrium and are the first to make contact with the embryo. They’re like the gatekeepers, and if these cells aren’t ready, implantation can’t start.
- Glandular epithelium: These glands are made up of deeper cells in the endometrium that provide nutrients and support after the embryo attaches.
The implantation window may be shortened in endometriosis
In both those with and without endometriosis, PCX levels dropped in the surface epithelium at the expected time, during the mid-secretory phase of the menstrual cycle. This suggests that the surface of the uterus becomes receptive as it should, even in patients with endometriosis.
But things were different when they looked deeper at the glandular epithelium!
- In women without endometriosis, PCX remained high in the glands during the mid-secretory phase (receptive window) and only dropped later in the late secretory phase, as expected.
- In contrast, women with endometriosis showed a drop in PCX levels by the mid-secretory phase, indicating that the tissue might be transitioning out of the receptive state earlier.
When the researchers quantified this, they found that 95% of mid-secretory samples in the control group met the criteria for being in the receptive window, compared to only 38% in the endometriosis group (p= 0.001). This suggests that the implantation window may be shortened or shifted in women with endometriosis.
Endometriotic lesions outside the uterus cycle like the uterus
The researchers also studied PCX expression in endometriotic lesions found outside the uterus (like on the bladder, cervix, and peritoneal wall).
They found that these cells also lost PCX at the same time as the uterus normally would. In other words, these endometrial lesions still respond to the menstrual cycle, as if they were part of the uterus.
This cycling likely makes these lesions more adhesive, making them become sticky when PCX drops. The cyclic drop in PCX might cause them to stick to nearby organs and form painful adhesions, which are common in endometriosis.
To test this idea, the researchers ran an adhesion experiment. They grew mesothelial cells in the lab and added endometrial epithelial cells with either high or low PCX expression. The cells with low PCX were significantly more likely to stick, suggesting that PCX contributes to the “stickiness” of pelvic adhesions in endometriosis patients.
Conclusions
This study offers a new way to think about the timing of implantation in endometriosis. While the surface of the uterus appears to become receptive at the right time, the supportive glandular epithelium behind it may exit the receptive phase too early. That could make the implantation window shorter or less synchronized with embryo development, especially in natural cycles or in transfers timed based on standard protocols.
The authors note that the early loss of receptivity in the endometrium may be linked to hormonal imbalances or inflammation in endometriosis patients.
The study also highlights how endometriotic lesions mimic the behavior of the uterus, cycling through a receptivity-like state each month as PCX levels drop. This could promote adhesion formation that worsen endometriosis symptoms and potentially cause fertility problems.
More research is needed to confirm these findings, but if they hold true, they could help improve the timing of fertility treatments for women with endometriosis.
Limitations include that this study was based on tissue analysis rather than clinical outcomes (with uncertain impact on pregnancy success), small sample sizes in some cycle phases, reliance on histologic dating, and no data on prior hormone use.
Reference
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About Embryoman
Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.
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